# Recurrent MDM2 Amplification in the Spectrum of HMGA2-Altered Pleomorphic Adenoma, Atypical Pleomorphic Adenoma and Carcinoma Ex Pleomorphic Adenoma

## TL;DR

This study finds that MDM2 amplification is more common in HMGA2-altered pleomorphic adenomas that progress to cancer, suggesting a role in malignant transformation.

## Contribution

The study identifies a link between MDM2 amplification and malignancy in HMGA2-altered pleomorphic adenomas.

## Key findings

- MDM2 amplification was present in 78% of carcinoma ex pleomorphic adenoma cases.
- MDM2 amplification was enriched in HMGA2-altered pleomorphic adenomas compared to benign PLAG1-altered neoplasms.
- MDM2 analysis could help confirm malignancy in HMGA2-altered cases with cytonuclear atypia.

## Abstract

Pleomorphic adenoma is the most common neoplasm of the salivary glands. While the overall risk of malignancy is relatively low, a distinct molecular sub-group harboring HMGA2 alterations seems to show an increased risk of malignant progression to carcinoma ex pleomorphic adenoma.

This study investigates MDM2 amplification in HMGA2-altered pleomorphic adenoma, atypical pleomorphic adenoma, and carcinoma ex pleomorphic adenoma.

In this multicenter, retrospective case series analysis, we examined 37 cases of HMGA2-altered pleomorphic adenoma, carcinoma ex pleomorphic adenoma, and pleomorphic adenoma with atypical features. A total of 18 cases were included from our institutional archives, with 19 additional cases derived from published literature. The cases from our institutes were analyzed for MDM2 amplification using a stepped approach by immunohistochemistry and FISH.

Collectively, an MDM2 amplification was present in 27% of pleomorphic adenoma (4 of 15), compared to 78% of carcinoma ex pleomorphic adenoma (14 of 18) (p-value = 0.003). In the group of pleomorphic adenomas with atypical features, an MDM2 amplification was present in 50% of cases (2 of 4). These findings indicate an association between MDM2 amplification and malignancy. Strikingly, a mixed control group of 12 benign and malignant PLAG1-altered neoplasms showed no immunohistochemical staining for MDM2.

Immunohistochemical MDM2 expression, including MDM2 amplification, is enriched in the group of HMGA2-altered pleomorphic adenoma, and potentially plays role in malignant progression. This study highlights the importance of recognizing the molecular sub-group of HMGA2-altered pleomorphic adenomas and integrate MDM2 analysis into routine diagnostics to corroborate the cytonuclear atypia in these challenging cases.

The online version contains supplementary material available at 10.1007/s12105-025-01794-y.